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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

Author

Listed:
  • Elizabeth Haythorne

    (University of Oxford)

  • Maria Rohm

    (University of Oxford
    Helmholtz Center Munich)

  • Martijn Bunt

    (University of Oxford, Churchill Hospital
    Novo Nordisk A/S)

  • Melissa F. Brereton

    (University of Oxford)

  • Andrei I. Tarasov

    (University of Oxford, Churchill Hospital)

  • Thomas S. Blacker

    (University College London)

  • Gregor Sachse

    (University of Oxford)

  • Mariana Silva dos Santos

    (The Francis Crick Institute)

  • Raul Terron Exposito

    (University of Oxford)

  • Simon Davis

    (University of Oxford)

  • Otto Baba

    (Tokushima University Graduate School)

  • Roman Fischer

    (University of Oxford)

  • Michael R. Duchen

    (University College London)

  • Patrik Rorsman

    (University of Oxford, Churchill Hospital
    University of Göteborg)

  • James I. MacRae

    (The Francis Crick Institute)

  • Frances M. Ashcroft

    (University of Oxford
    University of Göteborg)

Abstract

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

Suggested Citation

  • Elizabeth Haythorne & Maria Rohm & Martijn Bunt & Melissa F. Brereton & Andrei I. Tarasov & Thomas S. Blacker & Gregor Sachse & Mariana Silva dos Santos & Raul Terron Exposito & Simon Davis & Otto Bab, 2019. "Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10189-x
    DOI: 10.1038/s41467-019-10189-x
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    Cited by:

    1. Elizabeth Haythorne & Matthew Lloyd & John Walsby-Tickle & Andrei I. Tarasov & Jonas Sandbrink & Idoia Portillo & Raul Terron Exposito & Gregor Sachse & Malgorzata Cyranka & Maria Rohm & Patrik Rorsma, 2022. "Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Yu-Te Yeh & Chandan Sona & Xin Yan & Yunxiao Li & Adrija Pathak & Mark I. McDermott & Zhigang Xie & Liangwen Liu & Anoop Arunagiri & Yuting Wang & Amaury Cazenave-Gassiot & Adhideb Ghosh & Ferdinand v, 2023. "Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Chen Weng & Anniya Gu & Shanshan Zhang & Leina Lu & Luxin Ke & Peidong Gao & Xiaoxiao Liu & Yuntong Wang & Peinan Hu & Dylan Plummer & Elise MacDonald & Saixian Zhang & Jiajia Xi & Sisi Lai & Konstant, 2023. "Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Vaibhav Sidarala & Jie Zhu & Elena Levi-D’Ancona & Gemma L. Pearson & Emma C. Reck & Emily M. Walker & Brett A. Kaufman & Scott A. Soleimanpour, 2022. "Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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